"Human in vivo model to study the role of a functional enteric nervous system on intestinal development and maturation"

项目摘要 新兴的数据已经确定肠神经系统（ENS）作为肠道屏障的关键调节器 功能协调发展的除了控制蠕动运动、胃肠血流和分泌物外，ENS 已显示增强肠上皮屏障（IEB）并调节肠通透性。 ENS的变化主要见于IEB功能改变的胃肠道疾病。然而，在这方面， ENS对IEB病变的分子和细胞效应之间的联系仍然是难以捉摸的，主要是由于 缺乏模型。在此背景下，具有ENS的人类肠的开发代表了一个真实的 有机会扩大我们对ENS对肠道发育的影响的认识， 了解导致消化系统疾病的病理生理过程。我们最近开发的方法 以产生功能性人肠，结合独特的移植模型，提供了一种新的， 理想的实验方法在这个先前的模型的基础上，我们生成了一个复杂的人类肠道， 重新组装ENS特征以检验人ENS调节肠发育的假设， 生长和成熟。 这项拨款申请带来了另一个层次的创新，以胃肠道类器官系统的组织工程， 肠神经系统这项建议有三个主要方面。准确地说，我们将定义ENS 人类肠道类器官发育成完全分层和功能成熟的机制 肠（目标1）。我们将确定肠腔内容物对ENS表型的影响， 相关功能（目标2）。最后，我们将描述先天性ENS缺陷对 导致胃肠功能障碍肠道发育（目标3）。这项研究计划将允许 这是未来人类ENS控制GI功能和疾病的分子基础的前所未有的研究。 为了成功实现上述目标，一个由导师、合作者和 顾问将在研究战略和其他培训领域提供指导， 个人、技术和管理技能。此外，我将获得额外的培训和课程工作， 我成功地完成了这项提案，并向一个成功的独立科学家过渡。 事业 导师 迈克尔·A. Helmrath，MD，MS -辛辛那提儿童医院医疗中心，辛辛那提，OH，美国 詹姆斯·M.威尔斯，博士，辛辛那提儿童医院医疗中心，辛辛那提，俄亥俄州，美国 合作者 Michel Neunlist博士，博士-国家卫生和医学研究所（NationalInstituteofHealth and Medical Research）- Unit 913 肠神经系统和消化系统疾病的神经病变，南特，法国 顾问 PR.马歇尔H.蒙特罗斯，博士-美国俄亥俄州辛辛那提，辛辛那提大学 博士Ajay Kaul，医学博士-辛辛那提儿童医院医疗中心，辛辛那提，俄亥俄州，美国 博士诺亚湾Shroyer博士-美国德克萨斯州休斯顿贝勒医学院 裁判 博士西恩河摩尔，医学博士，理学硕士-辛辛那提儿童医院医疗中心，辛辛那提，俄亥俄州，美国 博士Jason Spence，博士-密歇根大学医学院，-美国密歇根州安港 博士Yana Zavros，博士-辛辛那提大学-辛辛那提，俄亥俄州，美国

Project Summary Emerging data has identified the enteric nervous system (ENS) as a key regulator of intestinal barrier functions. Besides the control of peristaltic movements, gastrointestinal blood flow and secretions, the ENS has been shown to reinforce the intestinal epithelial barrier (IEB) and modulate intestinal permeability. Changes in ENS have largely been described in gastrointestinal diseases with altered IEB functions. However, the link between the molecular and cellular effects of the ENS on IEB lesions still remains elusive mainly due to the lack of models. In this context, the development of human intestine with an ENS represents a real opportunity to expand our knowledge into the effect of ENS on intestinal development and toward the understanding of pathophysiological processes leading to digestive diseases. Our recently developed methods to generate a functional human intestine, combined with unique transplantation models, provide a novel and ideal experimental approach. Building on this previous model, we generated a complex human intestine reassembling the ENS features to test the hypothesis that human ENS regulates intestinal development, growth, and maturation. This grant application brings another level of innovation to the GI organoid systems by tissue engineering in the enteric nervous system. This proposal has three major strands. Precisely, we will define the ENS mechanisms underlying human intestinal organoid development into a fully laminated and functional mature intestine (Aim 1). We will determine the influence of intestinal luminal contents on the ENS phenotype and its associated functions (Aim 2). Finally, we will characterize the impact of congenital defective ENS on the intestinal development that lead to gastrointestinal dysfunctions (Aim 3). This research plan will allow for unprecedented studies in the future of the molecular basis of human ENS control of GI functions and diseases. To successfully achieve the aforementioned goals, a multidisciplinary group of mentors, collaborators and consultants will provide guidance in the research strategy and other training areas such as grant writing, personal, technical and management skills. Additionally, I will get additional training and course work to succeed in the completion of the proposal and in my transition toward a successful independent scientific career. Mentors Pr Michael A. Helmrath, MD, MS - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Pr James M. Wells, PhD, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Collaborator Dr Michel Neunlist, PhD - National Institute of Health and Medical Research (INSERM) – Unit 913 Neuropathies of the Enteric Nervous System and Digestive Diseases, Nantes, France Consultants Pr. Marshall H. Montrose, PhD – University of Cincinnati, Cincinnati, OH, USA Dr. Ajay Kaul, MD - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Dr. Noah F. Shroyer, PhD – Baylor College of Medicine, Houston, TX, USA Referees Dr. Sean R. Moore, MD, MS - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Dr. Jason Spence, PhD - University of Michigan Medical School, - Ann Harbor, MI, USA Dr. Yana Zavros, PhD - University of Cincinnati - Cincinnati, OH, USA